Camptothecin derivatives are DNA-topoisomerase I inhibitors that have emerged as a prominent class of anticancer agents. Together with the taxanes, the topoisomerase I inhibitors are presumably the most important new class of anticancer drugs introduced into clinical practice. Pre-clinical studies demonstrated significant in vitro and in vivo activity of topoisomerase I inhibitors, such as camptothecin and its derivatives, on a broad range of tumors. The results from clinical trials were promising, as shown by the registration of two topoisomerase inhibitors, topotecan and irinotecan (also known as CPT-11), in many European countries and in the USA, for treatment of patients with ovarian and colorectal cancer, respectively. Other derivatives are currently at different stages of clinical development.
In patent application EP1044977 and in J. Med. Chem. 2001, 44, 3264-3274, camptothecin derivatives are described which bear an alkyloxime O-substituted at position 7 and which are endowed with antitumor activity higher than the compound of reference topotecan. Moreover these camptothecin derivatives bearing an imino group on position 7, also show an improved therapeutic index. Among these compounds one of the preferred molecules was shown to be 7-t-butoxyiminomethylcamptothecin (CPT 184, also known as ST1481 or gimatecan).
Although the annual mortality rate of pediatric cancer has decreased over the past two decades, the proportion of deaths from tumors of the central nervous system in the same population has increased from 18 percent to 30 percent. The cause of childhood brain tumors is largely unknown. While radiation exposure is a recognized risk factor for brain tumors, the role of other environmental toxins is unclear in children. Less than 5 percent of pediatric brain tumors are associated with a known genetic disease, such as neurofibromatosis, a common genetic condition associated with benign tumor growths on nerve tissue (Serletis D, Parkin P, Bouffet E, Shroff M, Drake J M, Rutka J T J Neurosurg. 2007 106: 363-7).
Although only 1 percent of childhood brain tumors are detected at birth or in the first few months of life, a significant number are diagnosed before age five, suggesting a developmental defect. As a matter of fact, defects in developmental growth signaling pathways have recently been identified in embryonal tumors.
Historically, a diagnosis of brain cancer is provided by a pathologist, who views tissue samples under a microscope. Upon visual inspection of brain cells (histology), pathologists can then classify the tumor type (Miller C R, Perry A Arch Pathol Lab Med. 2007 131: 397-406). The limitations of this practice are that many brain tumors have a similar histology when they are actually very different tumors with greatly different prognoses and responses to therapies. There are some children diagnosed with medulloblastoma who respond well to therapy while others do not. Therefore, tumor classification is moving toward the use of molecular signatures to more precisely classify and grade tumor tissues (Sardi I Cavalieri D, Massimino M Paediatr Drugs. 2007 9:81-96).
In addition to confusing tumor classifications, in the past, pediatric tumors were considered to be similar to tumors in adults. However, recent studies have revealed that pediatric brain tumors are very different biologically than their adult counterparts. One example is a tumor called fibrillary astrocytoma, a tumor that occurs both in children and adults (Collins Nat Clin Pract Oncol. 2007 4: 362-74).
Biologically they behave very differently even though they look the same under the microscope. This disease in children rarely will become a high-grade tumor during childhood years, but in adults it can turn into higher grade tumors.
These observations are further supported by recent studies of molecular markers. Mutations in specific genes that cause disease in adults may not be the cause of disease in children. Future studies should provide fertile opportunities for drug target discoveries and related molecularly targeted therapies.
The use of surgery in treatment of pediatric brain tumors is well-established, but more effective treatments are needed. Imaging technologies have been used to non-invasively assess tumor status and treatment in children, thus eliminating the need to obtain repeated biopsies of the same tumor. The gains achieved in improved surgical resection of brain tumors also can be attributed to improved imaging technologies (Khatua S, Jalali R Pediatr Hematol Oncol. 2005 22: 361-71). Surgeons are now better able to locate a tumor and assess the margins, removing less of the normal brain tissue. This is a significant improvement because there is a direct correlation between the extent of tumor resection and survival in some types of brain tumors in pediatric patients. Improved imaging technologies have also spurred advances in radiation therapy techniques (Greco C Wolden S. Cancer. 2007 109: 1227-38). In addition to providing information about the size and location of a tumor, imaging techniques are also providing data to evaluate the biochemical profile of the tumor, as well. Studies have shown that changes in the ratio of certain biochemical components of a tumor can aid an oncologist in determining if a tumor is actively growing (Chen L, Madura K. Cancer Res. 2005 65:5599-606; Chung T D, Broaddus W C Mol Interv. 2005 5:15-9). These results would support the choice of aggressive or less stringent treatment regiments.
Blood flow to tumors and tissues in the brain is also being examined through imaging. Evaluation of changes in the amount of blood flowing to tissues in the brain is essential to assess the effectiveness of anti-angiogenic drugs. These drugs do not target the tumor directly, but attack the cells lining the blood vessels that support tumor growth. The tumor size may not shrink, but a decrease in the number of blood vessels surrounding the tumor is a significant advance (Kieran M W J Neurooncol. 2005 75: 327-34; Kibble A. IDrugs. 2007 10: 5-7). Anti-angiogenic drugs will most likely be combined with other agents that target the tumor directly. Currently, these agents are being tested alone for safety.
Neuroblastoma is one of the most common extracranial solid tumours in childhood with a poor prognosis in its advanced stage. Treatment failure is often associated to the occurrence of drug resistance. To date, treatment of pediatric neuroblastoma is still dismal, and therefore novel effective drugs are awaited. (Gutierrez J C, Fischer A C, Sola J E, Perez E A, Koniaris L G Pediatr Surg Int. 2007 23: 637-46). Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood, representing 5% of all childhood cancers (M. Beth McCarville, Sheri L. Spunt and Alberto S. Pappo AJR 2001; 176:1563-1569). It is thought to arise from primitive mesenchymal cells committed to skeletal muscle differentiation and can occur in a variety of organs and tissues, including those that lack striated muscle.
Primitive neuroectodermal tumors (PNETs) develop from primitive or undifferentiated neuroepithelial cells from the early development of the nervous system. PNET of the posterior fossa, or medulloblastoma, is the most common brain tumor in children. In 80% of cases, patients with PNETs develop acute hydrocephalus accompanied by severe symptoms of headache and vomiting, and they require urgent resection of the mass (de Bont J M, den Boer M L, Kros J M, Passier M M, Reddingius R E, Smitt P A, Luider T M, Pieters R. J Neuropathol Exp Neurol. 2007 66: 505-516).